Lower vs Higher Fluid Volumes in Adult Patients With Sepsis

Background IV fluids are recommended for adults with sepsis. However, the optimal strategy for IV fluid management in sepsis is unknown, and clinical equipoise exists. Research Question Do lower vs higher fluid volumes improve patient-important outcomes in adult patients with sepsis? Study Design and Methods We updated a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials assessing lower vs higher IV fluid volumes in adult patients with sepsis. The coprimary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. We followed the recommendations from the Cochrane Handbook and used the Grading of Recommendations Assessment, Development and Evaluation approach. Primary conclusions were based on trials with low risk of bias if available. Results We included 13 trials (N = 4,006) with four trials (n = 3,385) added to this update. The meta-analysis of all-cause mortality in eight trials with low risk of bias showed a relative risk of 0.99 (97% CI, 0.89-1.10; moderate certainty evidence). Six trials with predefined definitions of serious adverse events showed a relative risk of 0.95 (97% CI, 0.83-1.07; low certainty evidence). Health-related quality of life was not reported. Interpretation Among adult patients with sepsis, lower IV fluid volumes probably result in little to no difference in all-cause mortality compared with higher IV fluid volumes, but the interpretation is limited by imprecision in the estimate, which does not exclude potential benefit or harm. Similarly, the evidence suggests lower IV fluid volumes result in little to no difference in serious adverse events. No trials reported on health-related quality of life. Trial Registration PROSPERO; No.: CRD42022312572; URL: https://www.crd.york.ac.uk/prospero/

IV fluids are considered essential in the management of sepsis, but because current guidelines are supported by very low certainty evidence, 1 additional research is warranted.3][4][5][6][7][8] A previous version of this systematic review with meta-analysis of lower vs higher IV fluid volumes in adults with sepsis reported very low quantity and certainty of evidence. 9Hence, the strategies for IV fluid management in sepsis have been dominated by clinical equipoise.Several RCTs of fluid therapy in sepsis have been published, [10][11][12][13] which substantially increases the quantity of evidence.Therefore, we conducted an updated systematic review with metaanalysis to provide a summary of the available evidence on patient-important outcomes of lower vs higher IV fluid volumes in adult patients with sepsis.

Study Design and Methods
We updated the previously published systematic review according to a prespecified, updated protocol registered in the International Prospective Register of Systematic Reviews, PROSPERO. 14Details on protocol specifications and deviations are provided in e-Appendix 1.We followed the recommendations by the Cochrane Handbook 15 ; used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach 16 ; and reported the paper according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (checklist in e-Appendix 2). 17

Types of Studies
We included RCTs comparing different strategies intended to obtain a separation in IV fluid volumes in hospitalized adults with sepsis.We imposed no restrictions regarding language, publication source, or status.We excluded quasi-randomized trials because of selection bias and crossover trials because of the nature of the design. 14

Types of Participants
Participants included adult patients with sepsis (as defined in the original trials) independent of hospital setting.Trials restricted to children were excluded.

Types of Interventions
We included RCTs with a preplanned strategy for separation of IV fluid volumes or balances regardless of whether a separation was obtained. 14Trials using hemodynamic parameters as triggers for IV fluid administration were included, whereas trials with hemodynamic parameters as targets were excluded.We also excluded trials comparing different types of fluids and trials of resuscitation of severe blood loss and burns.

Type of Outcome Measures
We assessed the following preplanned outcomes at the time closest to 90 days.
Primary Outcomes: We had the following three coprimary outcomes: (1) all-cause mortality, (2) proportion of patients with one or more serious adverse events (SAEs) (as defined in the original trials or any untoward medical occurrence that fulfills the International Council on Harmonization Guideline for Good Clinical Practice [ICH-GCP] definition 18 ), and (3) health-related quality of life.
Secondary outcomes: Secondary outcomes included duration of mechanical ventilation, ventilator-free days, duration of vasopressor or inotropes, vasopressor-free days, use of renal replacement therapy (RRT), duration of RRT, RRT-free days, and incidence of acute kidney injury (AKI).
Exploratory outcomes: Exploratory outcomes included transfusion with any form of blood products, ICU length of stay, and hospital length of stay.

Search Methods for Identification of Studies
We systematically searched the Cochrane Library (2022, Issue 9), MEDLINE (1946 onward), Embase (1974 onward), Science Citation Take-home Points Study Question: In adult patients with sepsis, do lower fluid volumes compared with higher fluid volumes improve patient-important outcomes?Results: The relative risk of the coprimary outcomes was 0.98 (99% CI, 0.89-1.10)for all-cause mortality; for serious adverse events it was 0.95 (99% CI, 0.83-1.07) in the lower vs higher fluid groups; and no trials reported on health-related quality of life.Interpretation: Among adult patients with sepsis, lower IV fluid volumes probably result in little to no difference in all-cause mortality compared with higher fluid volumes, but the interpretation is limited by imprecision in effect estimates, which does not exclude potential benefit or harm.Similarly, the evidence suggests that lower IV fluid volumes result in little to no difference in serious adverse events.
Index Expanded and Conference Proceedings Citation Index (1990 onward), BIOSIS Previews (1969 onward), and Epistemonikos (no year-based restriction).The last search was performed September 6, 2022 (last search in the previous review was conducted on April 29,  2019).In addition, we searched for ongoing trials in clinical trial registers (ie, ClinicalTrials.gov,EU Clinical Trials Register, World Health Organization International Clinical Trials Registry Platform search portal).The full search strategy is available in e-Appendix 3.

Data Collection
Study Selection: Two of three investigators (P.S., K. L. E., or M. K. J.) screened articles independently and in duplicate for inclusion based on titles and abstracts.Potentially eligible articles were independently and in duplicate evaluated in full text by two investigators (P.S., K. L. E., or M. K. J.).Disagreements were resolved by discussion with a third senior author (M.H. M. or A. P.).
Data Extraction and Management: Two authors independently and in duplicate extracted data using a standardized data extraction form (P. S., K. L. E., M. K. J., T. S. M., M. C.) (e-Appendix 4).Extracted data items included trial characteristics (year of publication, country, and inclusion period), characteristics of trial population (inclusion and exclusion criteria), intervention and control (types of fluids used, criteria for administering fluids, volumes of resuscitation fluids, total fluid input, use of diuretics or fluid removal by RRT, and fluid balance over the study period), and data on the predefined outcomes.If prespecified data were not available, corresponding authors were contacted for further data at least twice.3][19][20][21][22][23][24][25][26] Risk of Bias: Two authors (P.S., K. L. E., or M. K. J.) independently assessed the risk of bias for all outcomes of the included trials using the revised Risk of Bias 2 tool by the Cochrane Collaboration. 15,27Risk of bias was assessed by P. S. and K. L. E. in one trial in which M. K. J. was first author, 13 and equally K. L. E. and M. K. J. assessed risk of bias for the trial in which P. S. was involved. 12Disagreements were resolved by discussion with a third author (A.G. or M. H. M.).We assessed the following five bias domains for each outcome in the included trials: (1) bias arising from the randomization process, (2) bias because of deviations from intended interventions, (3) bias because of missing outcome data, (4) bias in measurement of the outcome, and (5) bias in selection of the reported results.The overall risk of bias adjudication for each specific outcome was based on all five domains (ie, trial outcomes with low risk of bias in all five domains were judged as having overall low risk of bias; trials with one or more domains with some concerns were adjudicated as having overall some concerns or high risk of bias; and if one or more domains were judged as having high risk of bias, we classified it as having overall high risk of bias).
Our primary conclusions were based on trials with low risk of bias with estimates for all trials also presented.We used the pooled estimate of trials with some concern for SAEs because we found no trials with low risk of bias.

Statistical Analysis
Data Synthesis: We used R version 4.1.2(R Core Team, R Foundation for Statistical Computing) to conduct the conventional meta-analyses using the meta R package, whereas Bayesian analyses were conducted using R version 4.1.3and Stan version 2.29.2 28 through the brms R package. 29We used Trial Sequential Analysis version 0.9.5.10 beta (Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet; available from http://www.ctu.dk/tsa) to conduct the trial sequential analyses (TSAs).
Meta-analysis: Intention-to-treat (ITT) populations were used if available; otherwise, we used data from the modified ITT populations, as defined in the original trials.
Dichotomous outcomes were analyzed as relative risks (RRs), whereas continuous outcomes were analyzed as mean differences, both with 97% CIs for primary and exploratory outcomes and 99% CIs for secondary outcomes, respectively.Analyses were conducted using the raw numbers (dichotomous outcomes) and raw means and SDs (continuous outcomes) in each group.
We used both random effects models (assuming the true intervention effects are not identical in the included trials, but follow a normal distribution) and fixed effect models (assuming the true intervention effect is fixed in both direction and magnitude in the included trials), and reported the most conservative estimate according to highest P value. 14,30We considered P < .033,P < .0125,and P < .025statistically significant for primary, secondary, and exploratory outcomes, respectively, because of protocolized adjustment for multiplicity based on the number of outcomes (e-Appendix 5). 14 estimated the number of patients with one or more SAEs in three different analyses.Highest proportion of SAEs or serious adverse reactions (as defined in the original trial) was available in six out of 13 trials.These data were used in the primary analysis of SAEs and in the subgroup and sensitivity analyses for missing data.Further two analyses were conducted in line with the analyses of SAEs in the previous review with the highest proportion of SAEs, including mortality based on ICH-GCP definition and the cumulated number of reported SAEs 9 (e-Appendix 6, e-Tables 1-4).
Assessment of Heterogeneity: Forest plots were assessed for overlap of CIs between the trials.Moreover, heterogeneity was assessed with the inconsistency (I 2 ) and diversity (D 2 ) statistics. 15,31Potential heterogeneity was addressed in the planned subgroup analyses.

Assessment of Publication Bias:
We assessed publication bias for outcomes with at least 10 trials included using the Harbord test for a funnel plot asymmetry considering P < .05 as statistically significant. 32sessment of Risk of Random Errors: We used TSA to assess the risk of random errors for each outcome because of repetitive testing.TSA estimates the required information size (RIS) needed to detect or reject an a priori intervention effect in a meta-analysis and widens the CIs (TSA-adjusted CIs) in analyses when the RIS has not been reached. 31We applied trial sequential monitoring boundaries based on previous findings, 33 and our definitions on clinically important effects were protocolized 14 according to an a priori 15% RR reduction for dichotomous outcomes and a mean difference of 1 day, 24 h, or 1 unit of RBCs for the secondary or exploratory outcomes.
To match a family-wise error rate of 5%, we used an a of 3.3%, 1.25%, and 2.5% for primary, secondary, and exploratory outcomes, respectively (e-Appendix 5).A b of 10% (90% power) was used, and for binary outcomes we set the unweighted control event proportions as per the included trials, and used the empirical variances for continuous outcomes.For the random effects models heterogeneity adjustment was based on the increase in model variances changing from a fixed effect model to a random effects model (D 2 ).This was set to 0% in the fixed effect models. 14ssing Data: We conducted sensitivity analyses for patients who were lost to follow-up or excluded in the modified ITT populations with best-worst case scenarios and worst-best case scenarios. 14bgroup Analyses: We conducted the following six preplanned subgroup analyses: (1) overall low vs some concern or high risk of bias, (2) successful vs unsuccessful separation in fluid volumes as author-defined in each study, (3) patients with sepsis vs septic shock, (4) fluid-only interventions vs complex hemodynamic protocols, (5) earlier vs later resuscitation phase of sepsis, and (6) medical vs surgical treatment. 14Definitions of subgroups including the hypothesized direction of effect are available in the protocol. 14We used the c 2 test to assess the statistical heterogeneity across subgroups considering P ¼ .10 as significant.
Bayesian Analysis: We conducted a secondary Bayesian analysis of all trials reporting the coprimary outcome, all-cause mortality, which was prespecified in the updated systematic review PROSPERO registration, but not included in the previously published protocol for the original version of this systematic review 14 (e-Appendix 1).Bayesian fixed effect and random effects meta-analyses of all-cause mortality were conducted by analyzing crude RRs (with their SEs, both on the log RR scale) from the included trials.The primary analyses used weakly informative priors for the treatment effects.Details on priors and model diagnostics are provided in e-Appendix 6. Results are summarized using the median RRs from the posterior distributions as point estimates with 95% percentilebased credible intervals.
Assessment of the Overall Certainty of Evidence: Two authors (P. S. and K. L. E.) independently assessed the certainty of evidence using the GRADE methodology. 34The overall certainty of evidence was rated high, moderate, low, or very low based on evaluation of identified risks of bias, inconsistency, indirectness, imprecision, and publication bias.

Risk of Bias
An overview of risk of bias for all outcomes including adjudications is provided in e-Table 6.For all-cause mortality, one trial was judged as having overall high risk of bias, four trials were judged as having some concern for risk of bias, and the remaining eight trials were judged as having overall low risk of bias.Some concern/high risk of bias was because of the domains: bias in selection of the reported results and bias because of deviations from intended intervention.All six trials reporting SAEs were judged as having overall some concerns, mainly because of risk of bias in measurement of the outcome.For the secondary and exploratory outcomes, trials classified as having some concerns were because of bias in selection of the reported results and bias in measurement of the outcome.

Primary Outcomes
[20][21][22][23]25 Meta-analysis of the eight trials showed an RR of 0.99 (fixed effect model; 97% CI, 0.89-1.2). The subgroup analses and sensitivity analyses for missing data were consistent with the primary estimates (e-Tables 7-9, Fig 3).The full posterior probability distribution for the treatment effect for all trials is presented in Figure 4 (details in e-Appendix 6 and e-Figs 1-5).In the primary Bayesian analysis of mortality for all trials, the RR was 0.98 (fixed effect model; 95% percentile-based credible interval, 0.90-1.07).The probability of any benefit (ie, RR < 1.00) with lower IV fluid volumes was 66.1%, whereas the probability of effect sizes smaller than an RR reduction of 15% (or the opposite RR increase) with lower IV fluid volumes was > 99.9%.The probability of an RR reduction of at least 15% was 0.1%, whereas the probability of the corresponding RR increase (ie, RR $ 1.18) was < 0.1%.
SAEs: Six trials had defined and reported SAEs (n ¼ 3,600) [10][11][12][13]20,23 and showed an RR of 0.95 (fixed effect model; 97% CI, 0.83-1.07; P ¼ .8)(Fig 5A ) for the difference in SAEs between lower vs higher fluid volumes.The TSA showed that 46% of the RIS of 7,788 patients was accrued (TSA-adjusted CI, 0.78-1.15)(Fig 5B).The certainty of evidence was low because of imprecision and risk of bias because all trials were adjudicated as having some concerns (Table 2).The subgroup analyses and sensitivity analyses for missing data were consistent with the primary estimates (e-Tables 7-9).Analyses of the highest proportion of SAEs including mortality based on ICH-GCP and cumulated SAEs are provided in e-Appendix 6.
Health-Related Quality of Life: No trials reported data on health-related quality of life.
23,26 No statistically significant difference between lower vs higher fluid volumes was observed in the meta-analysis of three trials with low risk of bias (fixed effect model; mean difference, 0.00 h; 99% CI, À0.33 to 0.33; P > .99).TSA highlighted that more than the RIS had been accrued, and the cumulative z curve crossed the boundary of futility (e-Appendixes 7, 7.3).Therefore, a predefined MD of 24 h is unlikely with high certainty of evidence.
Vasopressor-free days were reported in six trials, of which data from five trials allowed for meta-analysis (n ¼ 3,324). 10,12,19,21,23,25Meta-analysis of three trials with low risk of bias showed no statistically significant difference between lower vs higher fluid volumes (fixed effect model; mean difference, 0.43 days; 99% CI, À0.68 to 1.53).In total, 38% of the RIS of 8,378 patients was accrued (TSA adjusted CI, À1.41 to 2.27) (e-Appendixes 7, 7.4).The certainty of evidence was moderate because of imprecision.
Duration of RRT was reported in three trials (n ¼ 1,753), 12,13,23 which were all at low risk of bias.The meta-analysis showed no statistically significant difference between lower vs higher fluid volumes (fixed effect model; mean difference, À0.17 days; 99% CI, À0.70 to 0.37).The TSA highlighted that the RIS of 1,013 patients was accrued, and the cumulative z curve crossed the boundary of futility.Therefore, a predefined MD of 1 day is unlikely (e-Appendixes 7, 7.6).The certainty of evidence was high.
We did not observe a statistically significant difference between lower vs higher fluid volumes (fixed effect model; mean difference, 0.46; 99% CI, À0.68 to 1.61).
The TSA highlighted that 35% of the RIS of 9,283 patients was accrued (TSA adjusted CI, À1.50 to 2.43).The certainty of evidence was moderate because of imprecision.(e-Appendixes 7, 7.7) AKI: Three trials reported the incidence of AKI as part of SAEs (n ¼ 1,754). 12,13,21Meta-analysis of two trials with low risk of bias showed an RR of 0.94 (fixed effect model; 99% CI, 0.75-1.19)for the difference between lower vs higher fluid volumes.The TSA displayed that 22% of the RIS of 7,633 patients was accrued (TSAadjusted CI, 0.46-1.93).The certainty of evidence was judged to be moderate because of imprecision.
Three trials either reported the Acute Kidney Injury Network score or Kidney Disease Improving Global Outcomes score. 20,23,25However, these were not included in the meta-analysis because of the reported worsening, and not incidence, of AKI.

Exploratory Outcomes
Meta-analysis of all three exploratory outcomes showed no statistically significant difference between lower vs higher fluid volumes.Further details are provided in e-Appendix 8.The TSA of three trials with low risk of bias reporting the use of blood products showed that the RIS (n ¼ 47) was reached within the first trial, and the cumulative z curve crossed the boundary of futility.Therefore, a mean difference of 1 unit of blood product is unlikely with high certainty of evidence (e-Appendixes 8, 8.1).The TSA of six trials with low risk of bias reporting ICU length of stay showed the cumulative z curve crossed the boundary of futility (TSA adjusted CI, À1.07 to 0.40), and 87% of the RIS was accrued.Therefore, a mean difference of 1 day is (Continued) eight low RoB trials.We used a control event proportion of 31.1%, a of 3.3% (two-sided), b of 10% (power 90%), and an a priori relative risk reduction of 15% in the analysis.The TSA-adjusted CI in the fixed effect model was 0.89 to 1.11 with a diversity D 2 of 0%.The blue cumulative z curve crossed the area of futility.Therefore, the TSA is conclusive, and a relative risk reduction of 15% is unlikely.A total of 83% (n ¼ 3,626) of the required information size of 4,380 patients was accrued.MH ¼ Mantel-Haaenszel; RRI ¼ relative risk increase; RRR ¼ relative risk reduction.TSA highlighted that the boundary for futility crossed and RIS was reached, thus the adjusted CI is identical to the unadjusted.Thus, we can exclude a predefined mean difference of 1 day.
e TSA highlighted that 34% of RIS was reached.Adjusted CI was À1.86 to 2.27.f TSA highlighted that the boundary for futility crossed and RIS was reached; therefore, the adjusted CI is identical to the unadjusted.Therefore, we can exclude a predefined mean difference of 24 h.g TSA highlighted that 38% of RIS was reached.Adjusted CI was À1.41 to 2.27.h Jessen et al had zero events and was not included in meta-analysis or TSA.i TSA highlighted that 19% of RIS was reached.Adjusted CI was 0.49 to 2.04 (from 62 fewer to 127 more).j Jessen et al had zero events and was not included in meta-analysis or TSA.The remaining three trials are low RoB trials.k TSA highlighted that the boundary for futility was crossed and RIS was reached; therefore, the adjusted CI is identical to the unadjusted.Therefore, we can exclude a predefined mean difference of 1 d.l TSA highlighted that 35% of RIS was reached.Adjusted CI was À1.50 to 2.43.m TSA highlighted that 22% of RIS was reached.Adjusted CI was 0.46 to 1.93.n TSA highlighted that the boundary for futility was crossed and RIS was reached; therefore, the adjusted CI is identical to the unadjusted.Therefore, we can exclude a predefined mean difference of 1 unit of blood product.o TSA highlighted 87% of RIS was reached, and the boundary for futility was crossed based on a predefined MD of 1 d.Adjusted CI was À1.07 to 0.40.p TSA highlighted that 18% of RIS was reached.Adjusted CI was À4.60 to 6.15.
unlikely with moderate certainty of evidence (e-Appendixes 8, 8.2).Eighteen percent of the RIS was accrued for hospital length of stay (TSA adjusted CI, À4.60 to 6.15) (e-Appendixes 8, 8.3).The blue cumulative z curve did not cross the conventional monitoring boundaries for benefit, harm, or futility; therefore, the TSA is inconclusive.The certainty of evidence was moderate.

Subgroup Analyses and Sensitivity Analyses
The subgroup analyses and sensitivity analyses for missing data for the secondary and exploratory outcomes were consistent with the primary analyses (e-Appendix 9, e-Tables 7-9).The subgroup analysis on medical vs surgical treatment was not conducted because these details could not be extracted separately.

Discussion
In this systematic review of lower vs higher IV fluid volumes in adults with sepsis, we found that an RR reduction $ 15% on mortality is unlikely.Furthermore, the probability of effect sizes smaller than an RR reduction of 15% (or the opposite RR increase) with lower IV fluid volumes was > 99.9%.The occurrence of SAEs was predefined and reported in only six of the 13 trials, and the definitions varied across trials.We observed no statistically significant difference in SAEs with low certainty of evidence.No trials reported health-related quality of life.We could exclude a difference of 1 day in duration of mechanical, vasopressor, and RRT.

Perspectives
IV fluids are used in daily clinical practice in patients with sepsis.We can with moderate certainty rule out substantial effects on mortality with lower vs higher IV fluids among adults with sepsis.This could partially be caused by clinical practice having changed over the last 10 years leading to use of lower volumes of fluids.Furthermore, the results might be blurred because most patients received IV fluids before inclusion in most trials and only three trials included patients in the ED.Of note, the effects of the initial resuscitation fluid is assessed in ongoing trials. 39,46Importantly, our finding does not exclude small but important effects on mortality, which would be clinically relevant considering the global burden of sepsis.Lower IV fluid volumes may result in little to no difference in SAEs compared with higher IV fluid volumes, but the interpretation is limited by imprecision in effect estimates, which do not exclude potential benefit or harm.All trials reporting on SAEs were adjudicated with some concern of risk of bias.Importantly, SAEs are likely to be underreported and definitions across trials differed.Therefore, our knowledge is still limited.We Figure 4 -Bayesian analysis of all-cause mortality.Full posterior probability distribution for the treatment effect on all-cause mortality from the Bayesian analysis in a fixed effect model.We used a normally distributed weakly informative prior centered on no difference for the treatment effect (mean AE SD, 0 AE 1).Sensitivity analyses using different priors are reported in e-Appendix 6.The plot displays the relative difference (RR).An RR < 1 favors lower fluid volumes, whereas an RR > 1 favors higher fluid volumes.The upper subplot displays the cumulative posterior distribution, and therefore displays the probabilities (vertical axes) of various effect sizes (horizontal axis).The lower subplots display the entire posterior distribution, with the bold, vertical line indicating the median value (used as the point estimate) and the area highlighted in red indicating the percentile-based 95% credible interval.The vertical black line represents exactly no difference.The probability of any benefit (ie, RR < 1.00) with lower IV fluid volumes was 66.1%, whereas the probability of effect sizes smaller than an RR reduction of 15% (or the opposite RR increase) with lower IV fluid volumes was > 99.9%.The probability of an RR reduction of at least 15% was 0.1%, whereas the probability of the corresponding RR increase (ie, RR $ 1.  Figure 5 -A, B, Serious adverse events.A, Meta-analysis of the highest proportion of serious adverse events (as defined in the original trial) in six trials, all with some concerns in the risk of bias adjudication.The conventional meta-analysis demonstrated no statistically significant difference in serious adverse events with lower vs higher fluid volumes (fixed effect model; relative risk, 0.95; 95% CI, 0.83-1.07;I 2 ¼ 0%).B, Trial sequential analysis (TSA) of the highest proportion of serious adverse events in six trials.We used a control event proportion of 20.1%, a of 3.3% (two-sided), b of 10% (power 90%), and an a priori relative risk reduction of 15% in the analysis.The TSA-adjusted CI in the fixed effect model was 0.78 to 1.15, with a diversity D 2 of 0%.The blue cumulative z curve did not cross the conventional monitoring boundaries for benefit, harm, or futility; the TSA is therefore inconclusive.A total of 46% (n ¼ 3,602) of the required information size of 7,788 patients was accrued.MH ¼ Mantel-Haaenszel; RRI ¼ relative risk increase; RRR ¼ relative risk reduction chestjournal.orgfunction.Furthermore, a more systematic and pragmatic approach to the reporting of SAEs is highly warranted.

Strengths and Limitations
We updated the previously conducted review because inclusion of the latest four trials enrolling 3,385 patients substantially increased the quantity and certainty of evidence.In addition to the meta-analyses, we conducted extensive analyses including TSA to estimate the RISs and conclusiveness of the evidence according to predefined effect sizes for each outcome.We also conducted Bayesian analyses of all-cause mortality to nuance the results.Additionally, we adhered to the published protocol and preplanned statistical analysis plan 14 and the recommendations by the Cochrane Collaboration and GRADE. 15,16[17] Our review also has limitations.First, the separation of fluid volumes between the groups was unsuccessful in five trials, which may have contributed to the finding of no difference in the outcomes.However, the subgroup analyses of trials with separation of fluid volumes were in line with the primary analysis.Second, the definitions of sepsis and septic shock were not consistent across the trials, which may influence mortality because this varies according to the definitions used. 47However, the post hoc meta-analysis of trials using the Sepsis-3 definition 43 vs earlier sepsis definitions was consistent with the primary analysis of all-cause mortality.Third, heterogeneity in the patient population and interventions may have been present because seven trials included patients in the ICU, three trials included patients from the ED, and three trials included patients from both settings.Furthermore, some fluid trials used more complex protocols including a bundle of interventions.We allowed all types of IV fluid, and one trial used hydroxyethyl starch with well-known harms in patients with sepsis, 48 but neither the treatment effects nor the potentially important dose dependencies were accounted for.Taken together, heterogeneity in patient populations and interventions is likely, which might have blurred any effects.The subgroup analyses assessing sepsis vs septic shock and simple vs complex protocols were consistent with the primary analyses.Fourth, SAE is a challenging outcome because definitions vary across trials and SAEs are likely underreported.Therefore, we analyzed data from all trials by including mortality and cumulated SAEs, as done in the first version of the review. 14These were consistent with the primary analysis of SAEs.Fifth, the TSAs are conducted based on a predefined RR reduction or mean difference; therefore, smaller reductions or difference cannot be excluded.Finally, in the individual days without life support outcomes and exploratory outcomes, data were reported with wide SDs, which is likely caused by the typically nonnormal distributions of these outcomes.This could influence the models used for these outcomes because they assume that data are normally distributed.Hence, results for these outcomes should be interpreted with caution.

Interpretation
In this systematic review of adult patients with sepsis, lower IV fluid volumes probably result in little to no difference in all-cause mortality compared with higher IV fluid volumes, but the interpretation is limited by imprecision in the effect estimate, which does not exclude potential benefit or harm.Similarly, the evidence suggests that lower IV fluid volumes result in little to no difference in SAEs.However, the certainty of evidence was downgraded because of imprecision and risk of bias because all trials reporting on SAEs were adjudicated as having some concerns.No trials reported on health-related quality of life. Funding/Support

6 . 12 ,Figure 2 -
Figure2-A-B, All-cause mortality.A, Meta-analysis of all-cause mortality in eight trials with low risk of bias (RoB) and five some concern/high concern RoB trials.The conventional meta-analysis of low RoB trials showed no statistically significant difference on mortality with lower vs higher fluid volumes (fixed effect model; relative risk, 0.99; 97% CI, 0.89-1.10;P ¼ .69;I 2 ¼ 0%).B, Trial sequential analysis (TSA) for all-cause mortality in(Continued)

Figure 3 -
Figure3 -A, B, Subgroup analyses of coprimary outcomes.A, Relative risks with 97% CIs are shown for the all-cause mortality with lower vs higher IV fluid volumes among all the patients and the five predefined subgroups and one post hoc subgroup on the Sepsis-3 definition vs other definitions.B, Relative risks with 97% CIs for SAEs with lower vs higher IV fluid volumes among all the patients and three predefined subgroups.SAE ¼ serious adverse event.

TABLE 1 ]
Characteristics of the Included Trials

TABLE 1 ]
(Continued)Unless otherwise stated the standard definitions for sepsis and septic shock are used.

TABLE 2 ]
GRADE Evaluation of the Certainty of Evidence (Low Risk of Bias Trials Only)

TABLE 2 ]
(Continued)The area of futility to detect a predefined relative risk reduction of 15% was reached; however, the CI overlaps no effect, and we cannot exclude important benefit or harm.Adjusted CI was 0.89 to 1.11 (from 34 fewer to 34 more).ROBs were adjudicated as some concerns for all six trials based measurement of the outcome, deviations from intended intervention, or selection of the reported result.
Values are No. of patients, No. of patients (%), or as otherwise indicated.AKI ¼ acute kidney injury; MV ¼ mechanical ventilation; RIS ¼ required information size; RoB ¼ risk of bias; RR ¼ risk ratio; RRT ¼ renal replacement therapy; SAE ¼ serious adverse event; TSA ¼ trial sequential analysis.a TSA highlighted that 83% of RIS was reached.b d 18) was < 0.1%.RR ¼ risk ratio Future objectives within this research field would be to assess a smaller, but still clinically relevant, difference on mortality and in other patient-important outcomes, including health-related quality of life and cognitive P. S. receives funding from the Research Council of Rigshospitalet, Copenhagen, Denmark; and the Ehrenreich Foundation.The Department of Intensive Care, Rigshospitalet receives support for research projects from Fresenius Kabi, Pfizer (CP231465), and Sygeforsikringen 'danmark' (2020-0320) and conducts contract research for AM-Pharma.